Intrauterine growth restriction (IUGR) of the infant is a major cause of infant mortality and morbidity. Furthermore, research during the last decade provides compelling evidence that IUGR infants exhibit higher rates of coronary heart disease, type-2 diabetes, hypertension and stroke as adults. A majority of IUGR cases results from placenta insufficiency (PI), and it is our goal to develop an understanding of the underlying mechanisms of PI-IUGR, with the long-term aim of developing methods of intervention. Using a natural model of PI-IUGR in sheep, which shares many physiological and biochemical characteristics now documented in human IUGR pregnancies, we have observed both acute and chronic changes in placental gene expression as the IUGR pregnancy develops. Presently, it is our objective to determine the mechanisms of altered placental development that lead to PI-IUGR, focusing on the acute changes in placental development. 3 specific aims are planned: 1) To determine if uterine blood flow and oxygen uptake is acutely altered in the development of placental insufficiency; 2) To examine the cellular response within the IUGR placenta that leads to increased vascular endothelial growth factor expression; and 3) To examine the function of individual regulatory pathways responsible for acute up-regulation of vascular endothelial growth factor expression within the developing IUGR placenta. The first specific aim will assess uterine arterial and venous blood flow and uterine oxygen uptake to determine if reduced blood flow or excessive uterine hypoxia is the initial insults leading to placental insufficiency. Specific aims 2 and 3 will examine the expression and function of regulatory proteins expressed within placenta and isolated trophoblast cells, in response to hyperthermia. The information yielded by these experimental approaches will provide insight into early placental development of PI-IUGR pregnancies, and may provide the base information for the future development of methods to resurrect normal placental development.